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Introduction
Infection with
the human immunodeficiency virus (HIV) is a type of
hypercoagulable state that predisposes to the
development of serious and potentially life-threatening
thromboembolic disorders such as deep venous thrombosis,
pulmonary embolism, and arterial thrombosis. Reported
causes of thrombophilia in HIV-infected subjects include
antiphospholipid syndrome [1], increased platelet
activation [1], elevated homocysteinemia [2], elevated
plasma factor VII activity [2], lupus anticoagulant ]3],
activated protein C resistance [3], protein C deficiency
[3,4], and acquired protein S deficiency [4-10]. We
herein report our experience with 12 HIV-seropositive
subjects with laboratory-confirmed evidence of protein S
deficiency, with and without venous or arterial
thrombosis, and discuss the diagnostic approach to
hypercoagulability in HIV infection, and the clinical
management of thromboembolic complications in patients
with protein S deficiency.
Patients and Methods
We
retrospectively reviewed the medical records of 12 HIV-seropositive
patients diagnosed with protein C and S deficiencies at
the Lawnwood Regional Medical Center and Heart
Institute, Fort Pierce, Florida, from July 2005 through
December 2005. All patients were seen by one of the
authors (DO), an infectious diseases consultant.
Lawnwood Regional Medical Center is a 341-bed, acute
care institution and regional referral center for four
counties of Treasure Coast, FL.
Hyperoagulability
testing was performed on all 12 subjects and included
protein C and S assays, lupus anticoagulant,
antiphospholipid antibodies, factor V Leiden,
antithrombin and homocysteine levels, and prothrombin
G20210A mutation. Protein S and C deficiencies were
the only coagulopathies detected. All subjects were
screened for common risk factors for thrombophilia
including family history, immobilization, recent surgery
or trauma, pregnancy, malignancy, and thrombogenic
medications such as conjugated estrogens or oral
contraceptives.
Results
Twelve
HIV-seropositive with laboratory-confirmed protein S
deficiency were identified, and their clinical features
are summarized (Table 1). Isolated protein S deficiency
was seen in 9 patients, and combined protein S plus
protein C deficiency occurred in 3 subjects. Other
primary or secondary risk factors for hypercoagulability
were not present. Five patients were asymptomatic, and
seven subjects had symptomatic, acute thromboembolic
manifestations including: deep venous thrombosis plus
pulmonary embolus (4 subjects), inferior vena cava
thrombosis (1 subject), deep venous thrombosis plus
inferior vena cava thrombosis (1 subject), and stroke (1
subject). Thromboembolic events were diagnosed using
venous angiodinograms and high resolution computed
tomography (CT) of the lung or abdomen. No patient had
previous thrombosis, family history of thrombosis, or
prothrombotic conditions. The mean patient age was 44
years (range, 21 to 60 years), and the male:female ratio
was 5:7. All subjects were African-American. The mean
CD4+ cell count was 102 per mm3 (range
0-343), and the mean HIV RNA level, determined by
polymerase chain reaction (PCR) testing, was 71,772
copies/mL (range 1,421-554,237 copies/mL). Only three
patients were receiving highly active antiretroviral
therapy (HAART) at the time of clinical presentation.
All symptomatic subjects received heparin, with or
without warfarin, for their thromboembolic event and all
but one recovered.
Discussion
Infection with HIV is an independent risk factor for
developing venous thromboembolic events. But HIV is
also associated with a variety of acquired
coagulopathies that increase the incidence of venous and
arterial thrombosis, including
antiphospholipid-anticardoplipin antibodies, increased
platelet activation, elevated serum homocysteine levels,
lupus anticoagulant, elevated plasma factor VII
activity, activated protein C resistance, protein C
deficiency, and protein S deficiency [1-10].
The prevalence of protein S deficiency among persons
with HIV infection has been reported in 33% to 94% of
patients with HIV infection [4-10].
A
study of protein S deficiency among 25 randomly-selected
HIV-seropositive men found 19 subjects (76%) with
decreased plasma free protein S levels, and this was a
statistically significant difference compared to healthy
male controls [9].
A
decrease in protein S levels did not correlate with CD4+
cell count, CDC class, p24 antigen positivity,
zidovudine use, or Pneumocystis carii
prophylaxis, but a linear correlation was seen with
duration of HIV infection. Sugerman and coworkers
conducted a prospective laboratory evaluation of 34
HIV-infected children and detected free protein S
deficiency in 76.5% of subjects; 55.9% had functional
protein S deficiency levels < 2SD below the mean of
laboratory controls [6].
These authors found no association between protein S
deficiency and CD4+ lymphocyte count, cy (CMV) status,
HIV p24 antigen, von Willebrand factor antigen, IgG
anti-cardiolipin antibodies, or serum
beta-2-microglobulin levels. Similarly, a prospective
study of 74 HIV-seropositive men found protein S
deficiency in 33% of the cohort, with no significant
association seen between protein S deficiency and
medication use, opportunistic infection, or CD4+ cell
count [7].
Bissuel et al. found plasma free protein S deficiency in
41 of 61 (65%) symptomatic and asymptomatic patients
infected with HIV-1, and a significant decrease in
plasma free protein S levels was observed in
HIV-seropositive subjects compared with healthy controls
(p = 0.0001) [10]. In contrast to the above
authors, however, protein S deficiency was associated
with disease severity, namely CD4+ lymphocyte count and
CDC class.
Sorice and coworkers also found that
protein S levels were significantly lower in patients
with < 100 CD4+ cells/ul compared to those with higher
counts [8].
Protein
S deficiency may result in venous thromboembolic
phenomena including deep venous thrombosis, pulmonary
embolus, inferior vena cava thrombosis, renal or hepatic
vein thrombosis, and intracranial venous and dural sinus
thrombosis [2,3,11,12], as well as arterial thrombosis
leading to stroke [3,13-17]. Still, there is a paucity
of data on the incidence of clinical thrombosis in
HIV-infected individuals with protein S deficiency.
Previous literature studies have reported thrombotic
events in 1.52% to 18% of HIV-infected patients with
protein S deficiency [3,7], but we found a 58% incidence
of clotting complications in our small study cohort.
Hassel et al reported an overall incidence of
thrombosis of 18% among 74 HIV-infected men, and
thrombosis developed in 6.6% of subjects followed
prospectively over a median follow-up of 12 months [7].
Development of thrombosis was not significantly
correlated with protein S levels. In a case-control
study, Mochan and colleagues found protein S deficiency
to be an epiphenomenon associated with HIV infection,
and it occurred significantly more frequently in
HIV-seropositive subjects compared to HIV-seronegative
patients with ischemic stroke (p < 0.001) [13].
However, when they included HIV-positive patients
without stroke as a control group and compared them with
the HIV-seropositive stroke group they found that
protein S deficiency was statistically related to HIV
infection but not to stroke occurrence. Among 35 black
South African heterosexuals with stroke, protein S
deficiency was the most common coagulopathy causing
clinical clotting abnormalities [14].
Highly active antiretroviral therapy (HAART) has altered
the expected frequency of hematologic complications in
HIV/AIDS [18].
Today, acquired
protein S deficiency is a relative rare complication of
HIV in the US among persons taking HAART, but is much
more common in developing regions of the world where
antiretroviral treatment is not as widely available.
Interestingly, however, the use of protease inhibitors
(PIs) has been implicated as the cause of a
hypercoagulable state in HIV-infected with myocardial
infarction [1]. Majluf-Cruz et al. reported a rate of
thrombosis of 1.52% (cumulative incidence = 0.30% per
year) during the 42-month follow-up period of their
study of 28 HIV-positive male homosexuals with venous
thrombosis, compared to a rate of 0.33% (cumulative
incidence = 0.055% per year; p < 0.001) in 600
patients in the pre-PI era [3]. Protein C and protein
S deficiency was detected in nine and two patients,
respectively, and lupus anticoagulant in one.
There
is almost no literature on the management of
HIV-seropositive patients with protein S deficiency and
thromboembolism. In subjects with clinical
thromboembolic events, we noted a good response to
treatment with heparin, with or without warfarin. One
previous study noted a high incidence of thrombotic
recurrences and hemorrhagic complications using oral
anticoagulants, and acetylsalicylic acid secondary
prophylaxis was successfully employed [3]. In view of
the 58% risk of thromboembolism in our small series of
HIV-seropositive patients, we suggest that screening of
asymptomatic individuals may be indicated, and those
with documented protein S deficiency may benefit from
aspirin primary prophylaxis, at least.
The pathogenesis of this HIV-related protein S
deficiency is poorly understood. Sorice and colleagues
screened for specific anti-protein S antibodies using
immunoblotting and showed an overall positivity of 28.6%
in HIV-seropositive patients, with a higher prevalence
in symptomatic than in asymptomatic patients [8].
Furthermore, the prevalence of positivity for
anti-protein S antibodies was higher in HIV-positive
subjects with protein S levels < 50%. Another group
evaluated the possible role of autoimmune mechanisms in
the pathophysiology of HIV-related acquired protein S
deficiency and detected anti-protein S antibodies in 31
(56.36%) of 55 HIV-1-positive patients vs. three (20%)
of 15 control subjects (p = 0.012) [19]. These
antibodies were associated with a significantly low
protein S activity compared to controls. Hooper and
colleagues postulated that tumor necrosis factor
(TNF)-downregulation of protein S may be a mechanism for
local and procoagulant activity and thrombosis in
patients with HIV/AIDS [20].
Conclusion
HIV-infected patients should be screened for acquired
protein S deficiency, which contributes to
hypercoagulability and risk of clinical thromboembolic
events. Asymptomatic patients with reduced plasma free
protein S levels may benefit from aspirin primary
prophylaxis.
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